This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The expression of a single odorant receptor (OR) gene from a large gene family in individual sensory neurons is an essential feature of the organization and function of the olfactory system. Individual olfactory sensory neurons in mice express only one of 1300 odorant receptor genes (Chess et al., 1994;Malnic et al., 1999). The choice of a specific odorant receptor defines the functional identity of a sensory neuron, and the receptor also provides an instructive cue that dictates the site of projection in the brain (Wang et al., 1998;Feinstein and Mombaerts, 2004;Barnea et al., 2004). Thus, the expression of a single receptor gene in a sensory neuron is an essential feature of olfactory perception. The goal of my research is to understand the mechanism of olfactory receptor gene choice. Olfactory sensory neurons (OSNs) express in a seemingly stochastic, monogenic and monoallelic fashion one out of 1400 olfactory receptor (OR) genes. We recently showed that OR loci are marked with the hallmarks of constitutive heterochromatin, trimethylation of lysines 9 and 20 of histones H3 and H4 respectively, in differentiating and fully differentiated OSNs. The deposition of these epigenetic marks on OR loci results in the formation of a chromatin structure with remarkable biochemical properties, such as extreme levels of compaction and unprecedented resistance to Dnase I digestion (Magklara et., al. submitted). Most likely, this unusual chromatin conformation assures that in each OSN the non-selected OR genes will become transcriptionally silent in the most effective and complete manner, as the "one receptor per neuron" rule is the cornerstone of mammalian olfaction. This chromatin-mediated silencing is fortified by the aggregation of the heterochromatic OR clusters in a few, distinct nuclear foci of transcriptionally silent chromatin.